Millions of women worldwide use injectable progestin-only contraceptives, primarily Depo-Provera and Norplant. These contraceptives have been shown to be highly effective with a very low rate of serious medical complications, but a high rate of irregular bleeding patterns, particularly in the first 6 to 12 months of use. Abnormal bleeding is the most common reason cited for method discontinuation, occurring in approximately 50% of Depo-Provera users and 15% of Norplant users by the end of the first year. The broad objectives of this proposal will be to evaluate a clinical strategy to prevent or reduce abnormal bleeding experienced by progestin-only contraceptors, and to better understand the hormonal mechanisms by which this bleeding is produced. The specific aim of this proposal include the following: 1) to analyze the efficacy of estrogen supplementation in reducing the incidence of abnormal bleeding in women by performing a prospective randomized clinical trial of estrogen supplementation vs. no estrogen in women who elect to initiate contraception with Depo-Provera or Norplant, 2) to identify prospective factors which are associated with patients at greatest risk of bleeding in this trial, 3) to evaluate the impact of spontaneous ovulation on the incidence of abnormal bleeding by periodic evaluation of a nested group of patients within the larger trial, and 4) to explore hormonal mechanisms responsible for abnormal bleeding in progestin-only contraceptors by determining the nature and patterns of estrogen and progesterone receptor expression in endometrium obtained from biopsies of patients in the nested study. An effective strategy to reduce the high rate of abnormal bleeding could produce significant clinical benefit in terms of patient satisfaction, a reduction of unscheduled visits to contraceptive clinics, and a lower rate of method discontinuation. Additionally, a better understanding of the hormonal mechanisms involved in abnormal bleeding would help establish a basis for further, more focused studies of endometrial events in breakthrough bleeding, and could lead to better clinical approaches and management strategies.